The likelihood of a chromosomally abnormal conception increases strikingly with age, and is a contributory factor in the age-related decrease in fertility in women. The basis of the age effect remains unknown, but recent molecular studies indicate that meiosis I (MI, the time at which homologous chromosomes segregate) is a critical time point in the genesis of most age-related trisomies. In this proposal we outline direct studies of human oocytes using cytological, cytogenetic, and molecular methodology to examine genetic recombination, spindle formation, and chromosome disjunction at MI. Recent advances in oocyte retrieval and In vitro maturation of oocytes now make such studies not only highly feasible, but also imperative if we are to understand the origins of the age-related increase in aneuploidy. Equally important, advances in molecular cytogenetics permit the identification of specific chromosomes at metaphase in these oocytes, so results can be obtained that are relevant to the chromosomes that most frequently malsegregate. The combined data from the proposed studies will provide information on the mechanism(s) responsible for the maternal age effect. Ultimately this knowledge may be useful in designing programs for clinical intervention. For example, if age-related changes in the periovulatory environment are found to increase the frequency of meiotic non-disjunction, then hormone therapy or In vitro maturation of oocytes may provide women over the age of 35 with art increased likelihood of achieving a normal pregnancy. This type of therapeutic intervention could ultimately shift the focus of reproductive health care for women over the age of 35 from prenatal diagnosis to detect abnormal pregnancies to preconception therapy to increase the likelihood of a normal pregnancy.